A Comparative Study between the Three Waves of the Pandemic on the Prevalence of Oropharyngeal Dysphagia and Malnutrition among Hospitalized Patients with COVID-19

Background: The phenotype of patients affected by COVID-19 disease changed between the waves of the pandemic. We assessed the prevalence of oropharyngeal dysphagia (OD), malnutrition (MN), and mortality between the first three waves of COVID-19 patients in a general hospital. Methods: a prospective observational study between April 2020–May 2021. Clinical assessment for OD was made with the volume-viscosity swallowing test; nutritional assessment was performed consistent with GLIM criteria. A multimodal intervention was implemented in the second and third wave, including (a) texturized diets—fork mashable (1900 kcal + 90 g protein) or pureed (1700 kcal + 75 g protein), (b) oral nutritional supplements (500–600 kcal + 25–30 g protein), and (c) fluid thickening (250 mPa·s or 800 mPa·s). Results: We included 205 patients (69.3 ± 17.6 years) in the 1st, 200 (66.4 ± 17.5 years) in the 2nd, and 200 (72.0 ± 16.3 years;) in the 3rd wave (p = 0.004). On admission, prevalence of OD was 51.7%, 31.3% and 35.1%, and MN, 45.9%, 36.8% and 34.7%, respectively; mortality was 10.7%, 13.6% and 19.1%. OD was independently associated with age, delirium, and MN; MN, with age, OD, diarrhea and ICU admission; mortality, with age, OD and MN. (4) Conclusions: Prevalence of OD, MN and mortality was very high among COVID-19 patients. OD was independently associated with MN and mortality. An early and proactive multimodal nutritional intervention improved patients’ nutritional status.


Introduction
The World Health Organization declared a global public emergency due to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) epidemic and the disease it causes, COVID-19 [1]. It was declared a pandemic in spring 2020, and caused high rates of both severely ill patients and mortality [2,3]. Fever, cough, sore throat, breathing difficulties and fatigue were the most common symptoms of the disease [2,3]. Its most common risk factors were age, the environment, unhealthy diets and lifestyles and the presence of previous chronic diseases such as diabetes, hypertension, obesity and immune system disorders. In sum, 80% of patients presented mild symptoms, 15% became grave, and finally 5% became critical with respiratory distress syndrome and multiorgan failure [4,5].
SARS-CoV-2 infection leads to a cytokine storm from different mechanisms, such as the activation of interleukins and macrophages. It generates an increased energy expenditure and the disruption of other mechanisms, adversely affecting the immune system and tissue repair [4,6]. Inadequate nutrition is common in these patients, particularly in the critically

Data Management and Statistical Analysis
Prevalence of OD, risk and prevalence of MN, total WL during hospital admission, and intrahospital mortality were the main outcome study variables. We also aimed to assess whether patients with OD and those with OD and MN had a worse prognosis

Data Management and Statistical Analysis
Prevalence of OD, risk and prevalence of MN, total WL during hospital admission, and intrahospital mortality were the main outcome study variables. We also aimed to assess whether patients with OD and those with OD and MN had a worse prognosis compared with those without these conditions. Two analyses were carried out: an initial descriptive analysis of all 605 patients included in the three waves of the pandemic, and a subsequent comparative analysis between the three waves.
Qualitative data were presented as relative and absolute frequencies analyzed using Fisher's exact test or the Chi-square test. Continuous data were presented as mean standard deviation (SD) and compared using the t-test (between-group comparisons) or paired t-test (within-group comparisons). For variables that did not follow a normal distribution, we used the non-parametric Mann-Whitney U test (between-group comparisons), the Wilcoxon test (within-group comparisons) or the Kruskal-Wallis test for multiple comparisons with Dunn's multiple comparisons test. To assess normality, we used the D'Agostino and Pearson omnibus normality test.
For bivariate analysis, the Chi-square test was used to assess the relationships between the different categorical factors with OD and MN (on discharge) and mortality (during hospital stay). For continuous factors, Student's t-test (normal distribution) and the Mann-Whitney U-test (non-normal distribution) were used. Multivariate models were performed with significantly associated factors (p < 0.05) and those clinically relevant to the different outcomes. The Stepwise method was used to assess independent factors. Functionality and weight change during the study period were calculated and plotted with data from surviving patients.
Results were interpreted according to the p-value obtained, the magnitude of the observed effect and its clinical and biological plausibility. Statistical significance was accepted for p-values < 0.05. Statistical analysis was performed with the specific language R (R Project for Statistical Computing; www.r-project.org; accessed on 15 September 2022).
Patients were hospitalized during a mean period of 12.7 ± 10.9 days. Up to 62% suffered from interstitial pneumonia, followed by a suspected bacterial infection in 10.8% of cases. Maximum mean fraction of inspired oxygen (FIO2) during hospitalization was 48.3 ± 31.3, 28.2% of them requiring high-flow oxygen venturi masks and 24.1% high concentration oxygen masks. In most cases, pharmacological treatment included antibiotics (42.9%); 8.2% of patients were referred to the ICU for a mean stay of 15.5 ± 14.0 days; 6.5% required orotracheal intubation for 14.4 ± 14.3 days, and overall intra-hospital mortality was 14.4%.

Figure 2.
Curves of admission during the three waves of the pandemic at Consorci Sanitari del Maresme, Catalonia, Spain. A dark gray shadow depicts hospitalization, and a light gray shadow depicts visits to the emergency department.

Three Waves Description
In the first wave, 205 patients were included, compared with the first 200 consecutively admitted patients in each one of the second and third waves ( Figure 3).

Three Waves Description
In the first wave, 205 patients were included, compared with the first 200 consecutively admitted patients in each one of the second and third waves ( Figure 3). ± 31.3, 28.2% of them requiring high-flow oxygen venturi masks and 24.1% high conc tration oxygen masks. In most cases, pharmacological treatment included antibiot (42.9%); 8.2% of patients were referred to the ICU for a mean stay of 15.5 ± 14.0 days; 6. required orotracheal intubation for 14.4 ± 14.3 days, and overall intra-hospital mortal was 14.4%.

Three Waves Description
In the first wave, 205 patients were included, compared with the first 200 conse tively admitted patients in each one of the second and third waves ( Figure 3). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). 28  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority o patients from the second and third waves came from the community, while the per centage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the firs wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves o COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009 than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospita stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. W found statistical differences with regard to age, particularly when comparing the secon and third waves (p = 0.004), with the oldest patients in the third wave. The majority o patients from the second and third waves came from the community, while the pe centage of patients that came from nursing homes and social health centers was higher i the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaire functional status, though slightly improved in the second wave (p = 0.012 between waves and only 51.1% to 63.0% of patients from the three waves were independent for dail living activities. Serious neurological symptoms were more prevalent during the firs wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the firs second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves o COVID-19 patients is described in Table 2. The main differences between waves show higher need for high-flux Venturi masks in the first and second waves (p < 0.001). Th mean peak FIO2 administered in the second and third waves was significantly highe than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU wa higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009 than in the second wave, where an increase in the use of nasal intermittent positiv pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospita stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially i the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. W found statistical differences with regard to age, particularly when comparing the secon and third waves (p = 0.004), with the oldest patients in the third wave. The majority patients from the second and third waves came from the community, while the pe centage of patients that came from nursing homes and social health centers was higher the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impair functional status, though slightly improved in the second wave (p = 0.012 between wave and only 51.1% to 63.0% of patients from the three waves were independent for dai living activities. Serious neurological symptoms were more prevalent during the fir wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the fir second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves COVID-19 patients is described in Table 2. The main differences between waves show higher need for high-flux Venturi masks in the first and second waves (p < 0.001). T mean peak FIO2 administered in the second and third waves was significantly high than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU w higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.00 than in the second wave, where an increase in the use of nasal intermittent positi pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospit stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially the third one (19.1%; p < 0.05 vs. 1st wave). Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is found statistical differences with regard to age, particularly when and third waves (p = 0.004), with the oldest patients in the third patients from the second and third waves came from the com centage of patients that came from nursing homes and social heal the 1st wave (p < 0.001 s and third vs. first wave). Patients from thr functional status, though slightly improved in the second wave (p and only 51.1% to 63.0% of patients from the three waves were living activities. Serious neurological symptoms were more pre wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% second and third waves, respectively (p < 0.001); headache in 28.3% 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Of 605 patients, only 10.6% were previously diagnosed with OD. On admission, 37.1% of patients referred to eating and/or drinking difficulties after the specific anamnesis and evaluation of OD. After the clinical assessment of OD with the V-VST, 39.6% were diagnosed with OD on admission, with 38.5% and 31.4% of patients presenting clinical signs of impaired efficacy and safety of swallow among the whole study population, respectively. Fluid adaptation was needed in 29% (35.8% at medium viscosity (250 mPa·s) and 3.8% at high viscosity (800 mPa·s) and diet, in 41.1% (23.4% fork-mashable and 27.3% pureed diet) of patients, respectively. On discharge, the prevalence of OD was slightly reduced at 35.7% (n = 210), as well as the need for fluid adaptation (14.8%) and texture modified diets (16.4%).

Three Waves Description
The swallowing function of patients from the three waves of COVID-19 is described in Table 3. Patients in the first wave reported significantly greater difficulties in eating and/or swallowing on admission (EAT-10 and OD anamnesis). After evaluation using the V-VST, 51.7% of patients from the first wave had OD on admission, vs. 31.3% and 35.1% in the second and third waves, respectively (p < 0.001). On discharge, OD prevalence was reduced in all waves but remained higher in patients from the first (p = 0.006) ( Table 3). Consequently, more patients in the first wave needed adaptation of fluids to medium viscosity on admission (p < 0.001) and to medium and high viscosity on discharge (p = 0.012) to avoid aspirations. No significant differences were observed with respect to prescription of texture modified diets either on admission or discharge between the three waves.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive 0.2 ± 0.9 *** <0.001 Previous diagnosis of OD, % (n/N) 9 al characteristics and the therapeutic approach of the three waves of patients is described in Table 2. The main differences between waves show a d for high-flux Venturi masks in the first and second waves (p < 0.001). The FIO2 administered in the second and third waves was significantly higher first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 s greater in the first wave. The percentage of patients admitted to the ICU was he first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) e second wave, where an increase in the use of nasal intermittent positive entilation was observed (p < 0.05). Patients in the first wave had longer hospital .001). Intra-hospital mortality was high among the three waves, especially in ne (19.1%; p < 0.05 vs. 1st wave). p < 0.05 vs. third wave. Bold indicates statistically significant. Underlined means nearly reaches statistical significance.

Total Participants
Almost all COVID-19 patients included in this study (98.9%) were at risk of MN on admission according to NRS2002 (score ≥ 3). On discharge, 39.1% were malnourished according to GLIM criteria. Most of the patients on admission were overweight (mean BMI = 28.7 ± 5.7 kg/m 2 ), but most of them reported having suffered WL before (63.0%) and during (62.0%) hospitalization, more specifically 2.1 ± 2.8 kg and 2.5 ± 4.5 kg, respectively. Total mean WL prior and during admission was 4.7 ± 5.2 kg. Only 26.6% (n = 114) of hospitalized COVID-19 patients conserved their appetite and ate a complete diet during the days prior to admission, which improved to 73.6% (n = 324) on discharge. ONS were prescribed to 74.0% with full adherence in only half of them (47.4%); 9.4% needed nasogastric tube feeding. Other prevalent symptoms during hospital stay that contributed to WL were: anorexia (23.8%, n = 107), vomiting and nausea (8.9%, n = 53), diarrhea (30.1%, n = 127) and incomplete diet intake (40.5%, n = 184).

Three Waves Description
Almost all patients from the three waves presented high nutritional risk on admission, as measured with the NRS 2002. However, during hospitalization, the prevalence of MN was higher in patients from the first wave (p < 0.05 vs. third wave). Moreover those from the first wave had higher prevalence of clinical symptoms contributing to impaired nutritional status such as vomiting or nausea and diarrhea. In contrast, ONS prescription was significantly lower in the first wave (<0.001) and nasogastric tube placement higher (p < 0.001) ( Table 4).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). graphic data of all patients included in each wave is detailed in Table 1. We stical differences with regard to age, particularly when comparing the second aves (p = 0.004), with the oldest patients in the third wave. The majority of om the second and third waves came from the community, while the perpatients that came from nursing homes and social health centers was higher in e (p < 0.001 s and third vs. first wave). Patients from three waves had impaired status, though slightly improved in the second wave (p = 0.012 between waves) 1.1% to 63.0% of patients from the three waves were independent for daily ities. Serious neurological symptoms were more prevalent during the first e pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. ographic characteristics of the first three waves of COVID-19 patients. al characteristics and the therapeutic approach of the three waves of patients is described in Table 2. The main differences between waves show a d for high-flux Venturi masks in the first and second waves (p < 0.001). The FIO2 administered in the second and third waves was significantly higher first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 greater in the first wave. The percentage of patients admitted to the ICU was he first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) e second wave, where an increase in the use of nasal intermittent positive ntilation was observed (p < 0.05). Patients in the first wave had longer hospital 001). Intra-hospital mortality was high among the three waves, especially in ne (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).
14, x FOR PEER REVIEW 7 of 20 Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). p < 0.001 vs. third wave. Bold indicates statistically significant. Underlined means nearly reaches statistical significance.
WL was significantly higher in the first wave with a higher percentage of patients losing more than 10 kg during hospitalization (19.2% first wave vs. 1.5% and 1.7% in the second and third waves, respectively; p < 0.0001) and a higher total WL from pre-admission to discharge (6.5 ± 5.8 kg 1st wave vs. 3.3 ± 4.2 kg and 4.1 ± 4.3 kg in the second and third waves respectively; p < 0.0001) ( Table 5).

Three Waves Description
Analytical parameters on admission and discharge in all the waves of the pandemic are detailed in Table 6. We observed significant differences in total proteins and lymphocytes on admission between the three waves. No significant differences were observed on admission with regard to cholesterol values; however, when patients were discharged, the ones in the second and third waves presented significantly lower values compared with the first wave (p < 0.05). Inflammatory status was higher in all the samples (according to CRP levels); however, on discharge, patients in the third wave presented significantly higher CRP compared with the first and second wave (p < 0.05). We didn't observe any significant differences in albumin and ferritin values.  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).
14, x FOR PEER REVIEW 7 of 20 Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001.  Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). data of all patients included in each wave is detailed in Table 1. We ferences with regard to age, particularly when comparing the second = 0.004), with the oldest patients in the third wave. The majority of second and third waves came from the community, while the perthat came from nursing homes and social health centers was higher in 01 s and third vs. first wave). Patients from three waves had impaired ough slightly improved in the second wave (p = 0.012 between waves) 63.0% of patients from the three waves were independent for daily rious neurological symptoms were more prevalent during the first ic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, aves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = in 15.1%, 3.5%, and 7.5%, p < 0.001. c characteristics of the first three waves of COVID-19 patients. cteristics and the therapeutic approach of the three waves of is described in Table 2. The main differences between waves show a h-flux Venturi masks in the first and second waves (p < 0.001). The dministered in the second and third waves was significantly higher ough the ratio between oxygen arterial pressure (PaO2) and the FIO2 in the first wave. The percentage of patients admitted to the ICU was ave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) wave, where an increase in the use of nasal intermittent positive was observed (p < 0.05). Patients in the first wave had longer hospital ra-hospital mortality was high among the three waves, especially in ; p < 0.05 vs. 1st wave). data of all patients included in each wave is detailed in Table 1. We fferences with regard to age, particularly when comparing the second p = 0.004), with the oldest patients in the third wave. The majority of second and third waves came from the community, while the perthat came from nursing homes and social health centers was higher in 001 s and third vs. first wave). Patients from three waves had impaired hough slightly improved in the second wave (p = 0.012 between waves) 63.0% of patients from the three waves were independent for daily erious neurological symptoms were more prevalent during the first mic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, aves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = in 15.1%, 3.5%, and 7.5%, p < 0.001. ic characteristics of the first three waves of COVID-19 patients. acteristics and the therapeutic approach of the three waves of s is described in Table 2. The main differences between waves show a gh-flux Venturi masks in the first and second waves (p < 0.001). The dministered in the second and third waves was significantly higher though the ratio between oxygen arterial pressure (PaO2) and the FIO2 in the first wave. The percentage of patients admitted to the ICU was wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) d wave, where an increase in the use of nasal intermittent positive n was observed (p < 0.05). Patients in the first wave had longer hospital tra-hospital mortality was high among the three waves, especially in %; p < 0.05 vs. 1st wave). c data of all patients included in each wave is detailed in Table 1. We ifferences with regard to age, particularly when comparing the second (p = 0.004), with the oldest patients in the third wave. The majority of second and third waves came from the community, while the pers that came from nursing homes and social health centers was higher in .001 s and third vs. first wave). Patients from three waves had impaired though slightly improved in the second wave (p = 0.012 between waves) o 63.0% of patients from the three waves were independent for daily erious neurological symptoms were more prevalent during the first emic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = m in 15.1%, 3.5%, and 7.5%, p < 0.001. hic characteristics of the first three waves of COVID-19 patients. racteristics and the therapeutic approach of the three waves of ts is described in Table 2. The main differences between waves show a igh-flux Venturi masks in the first and second waves (p < 0.001). The administered in the second and third waves was significantly higher lthough the ratio between oxygen arterial pressure (PaO2) and the FIO2 r in the first wave. The percentage of patients admitted to the ICU was wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) d wave, where an increase in the use of nasal intermittent positive on was observed (p < 0.05). Patients in the first wave had longer hospital tra-hospital mortality was high among the three waves, especially in %; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave). Demographic data of all patients included in each wave is detailed in Table 1. We nd statistical differences with regard to age, particularly when comparing the second third waves (p = 0.004), with the oldest patients in the third wave. The majority of ents from the second and third waves came from the community, while the pertage of patients that came from nursing homes and social health centers was higher in 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired ctional status, though slightly improved in the second wave (p = 0.012 between waves) only 51.1% to 63.0% of patients from the three waves were independent for daily g activities. Serious neurological symptoms were more prevalent during the first e of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, nd and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 4, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of VID-19 patients is described in Table 2. The main differences between waves show a er need for high-flux Venturi masks in the first and second waves (p < 0.001). The n peak FIO2 administered in the second and third waves was significantly higher in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 FI) was greater in the first wave. The percentage of patients admitted to the ICU was er in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) in the second wave, where an increase in the use of nasal intermittent positive ssure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital (p < 0.001). Intra-hospital mortality was high among the three waves, especially in third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Table 1. We found statistical differences with regard to age, particularly when comparing the second and third waves (p = 0.004), with the oldest patients in the third wave. The majority of patients from the second and third waves came from the community, while the percentage of patients that came from nursing homes and social health centers was higher in the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had impaired functional status, though slightly improved in the second wave (p = 0.012 between waves) and only 51.1% to 63.0% of patients from the three waves were independent for daily living activities. Serious neurological symptoms were more prevalent during the first wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in the first, second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17.5%, p = 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three waves of COVID-19 patients is described in Table 2. The main differences between waves show a higher need for high-flux Venturi masks in the first and second waves (p < 0.001). The mean peak FIO2 administered in the second and third waves was significantly higher than in the first, although the ratio between oxygen arterial pressure (PaO2) and the FIO2 (PAFI) was greater in the first wave. The percentage of patients admitted to the ICU was higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) than in the second wave, where an increase in the use of nasal intermittent positive pressure ventilation was observed (p < 0.05). Patients in the first wave had longer hospital stay (p < 0.001). Intra-hospital mortality was high among the three waves, especially in the third one (19.1%; p < 0.05 vs. 1st wave).  Demographic data of all patients included in each wave is detailed in Tabl found statistical differences with regard to age, particularly when comparing the and third waves (p = 0.004), with the oldest patients in the third wave. The maj patients from the second and third waves came from the community, while t centage of patients that came from nursing homes and social health centers was h the 1st wave (p < 0.001 s and third vs. first wave). Patients from three waves had im functional status, though slightly improved in the second wave (p = 0.012 between and only 51.1% to 63.0% of patients from the three waves were independent fo living activities. Serious neurological symptoms were more prevalent during t wave of the pandemic; confusion affected 40.0%, 14.6%, and 28.5% of patients in t second and third waves, respectively (p < 0.001); headache in 28.3%, 24.6%, and 17 0.034, and delirium in 15.1%, 3.5%, and 7.5%, p < 0.001. Clinical characteristics and the therapeutic approach of the three wa COVID-19 patients is described in Table 2. The main differences between waves higher need for high-flux Venturi masks in the first and second waves (p < 0.00 mean peak FIO2 administered in the second and third waves was significantly than in the first, although the ratio between oxygen arterial pressure (PaO2) and t (PAFI) was greater in the first wave. The percentage of patients admitted to the IC higher in the first wave (p < 0.05) with a higher rate of orotracheal intubation (p than in the second wave, where an increase in the use of nasal intermittent p pressure ventilation was observed (p < 0.05). Patients in the first wave had longer h stay (p < 0.001). Intra-hospital mortality was high among the three waves, espec the third one (19.1%; p < 0.05 vs. 1st wave). hic data of all patients included in each wave is detailed in Table 1. We differences with regard to age, particularly when comparing the second s (p = 0.004), with the oldest patients in the third wave. The majority of he second and third waves came from the community, while the pernts that came from nursing homes and social health centers was higher in 0.001 s and third vs. first wave). Patients from three waves had impaired s, though slightly improved in the second wave (p = 0.012 between waves) to 63.0% of patients from the three waves were independent for daily . Serious neurological symptoms were more prevalent during the first demic; confusion affected 40 aracteristics and the therapeutic approach of the three waves of nts is described in Table 2. The main differences between waves show a high-flux Venturi masks in the first and second waves (p < 0.001). The 2 administered in the second and third waves was significantly higher although the ratio between oxygen arterial pressure (PaO2) and the FIO2 ter in the first wave. The percentage of patients admitted to the ICU was st wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) ond wave, where an increase in the use of nasal intermittent positive tion was observed (p < 0.05). Patients in the first wave had longer hospital Intra-hospital mortality was high among the three waves, especially in .1%; p < 0.05 vs. 1st wave). hic data of all patients included in each wave is detailed in Table 1. We l differences with regard to age, particularly when comparing the second s (p = 0.004), with the oldest patients in the third wave. The majority of the second and third waves came from the community, while the pernts that came from nursing homes and social health centers was higher in < 0.001 s and third vs. first wave). Patients from three waves had impaired s, though slightly improved in the second wave (p = 0.012 between waves) to 63.0% of patients from the three waves were independent for daily s. Serious neurological symptoms were more prevalent during the first demic; confusion affected 40 haracteristics and the therapeutic approach of the three waves of ents is described in Table 2. The main differences between waves show a r high-flux Venturi masks in the first and second waves (p < 0.001). The 2 administered in the second and third waves was significantly higher , although the ratio between oxygen arterial pressure (PaO2) and the FIO2 ater in the first wave. The percentage of patients admitted to the ICU was rst wave (p < 0.05) with a higher rate of orotracheal intubation (p = 0.009) ond wave, where an increase in the use of nasal intermittent positive ation was observed (p < 0.05). Patients in the first wave had longer hospital . Intra-hospital mortality was high among the three waves, especially in 9.1%; p < 0.05 vs. 1st wave). phic data of all patients included in each wave is detailed in Table 1. We al differences with regard to age, particularly when comparing the second es (p = 0.004), with the oldest patients in the third wave. The majority of the second and third waves came from the community, while the perients that came from nursing homes and social health centers was higher in < 0.001 s and third vs. first wave). Patients from three waves had impaired us, though slightly improved in the second wave (p = 0.012 between waves) % to 63.0% of patients from the three waves were independent for daily s.

Multivariate Analysis: Independent Risk Factors Associated with OD, MN and Mortality
A multivariate logistic regression analysis showed that: (a) age, the presence of delirium, nutritional risk (NRS-2002 ≥ 3) and MN (GLIM criteria) were independently associated with OD (Table 7), all being risk factors for its development; (b) age, OD on admission, ICU admission, diarrhea and an incomplete diet on discharge were independently associated with MN during hospitalization (Table 7), and (c) age, OD on admission and MN (GLIM criteria) were independently associated with mortality during hospitalization (Table 7).

Discussion
The main aim of this study was to compare the prevalence of OD, MN and mortality between the three first waves of the pandemic in a general hospital and the impact of a systematic multimodal intervention, including fluid thickening, texture modified foods and nutritional support, on the clinical outcomes of these patients during hospitalization. We evaluated a total of 605 COVID-19 patients from the three first waves of the SARS-CoV-2 pandemic, a population constituted by older patients from the community with slightly impaired functionality and high prevalence of comorbidities. The main results found in the three waves showed that the prevalence of OD, MN and mortality was very high among hospitalized COVID-19 patients, that OD was independently associated with MN and mortality, and that an early, systematic and proactive multimodal nutritional intervention, "screen and treat," improved patients' nutritional status in the second and third wave.
The pathophysiology of OD in COVID-19 has been extensively studied and related to aging, neurological diseases, respiratory insufficiency, invasive respiratory support, sarcopenia and cachexia [33,34]. Sarcopenic dysphagia has been defined as a swallowing disorder due to sarcopenia involving the whole-body skeletal muscles and swallowing muscles [13]. It is characterized by decreased swallowing function [15], tongue strength and range of tongue motion, weakened pharyngeal muscle contraction and deteriorated endurance of swallowing muscles, all of which are the risk factors of dysphagia [15,35]. In patients affected by COVID-19, one must be aware of the existence of OD, even in the absence of intubation, and its association with increased morbidity and mortality. The need to incorporate swallow-function assessment as part of the daily clinical routine in older patients with COVID-19 affected with malnutrition and/or sarcopenia has been recommended [16]. On the other hand, the contribution of SARS-CoV-2 infection to the development of OD is presumed to be related to loss of taste and smell, common neurological symptoms in COVID-19 patients, as well as peripheral and central nerve invasion by the virus that may affect sensorimotor swallowing function [6,[10][11][12], and is probably related to glossopharyngeal and vagal sensory neuropathy [6,36] and to the functional, nutritional, neurological and general health deterioration caused by the disease [6,10]. We have previously studied the role of pharyngeal sensory alterations in the pathophysiology of OD and found that there is an impaired cortical conduction and integration of pharyngeal sensory afferents in post-stroke and older patients with OD [37][38][39], concluding that pharyngeal sensory information is of key relevance in its pathophysiology. In our present study, prevalence and new cases of OD on admission in the three waves of the pandemic was very high. However, the prevalence was significantly higher in the first wave (51.7% p < 0.001 vs. second 31.3% and third wave 35.1%). On discharge, swallowing impairment was still present in 43.8%, 28.6% and 34.4 of patients from the first, second and third waves, respectively, and in our first longitudinal study, prevalence of OD remained high during the 6-month follow up (23.3%) [8], showing OD is a major issue among COVID-19 patients. A comparative study between the first two waves of the pandemics performed in the Sunnyview Rehabilitation Hospital in USA found a similar prevalence of OD on admission in the first wave (47.1% vs. 51.7% in our study) and it was significantly reduced in the second wave (13.8%), which included patients significantly younger [40]. As in our case, the reduced prevalence in the second and third waves could be related to patient's age, as those in the second were younger compared to the first and third, to better management of patients, to the lower prevalence of neurological symptoms and use and need for high-flow oxygen and venturi masks which were more necessary in the first wave due to greater clinical severity, higher admission to the ICU and longer hospital stay. However, other studies have reported a lower prevalence of OD in a similar cohort of patients (28.9%) [9] and in post-extubated patients with COVID-19 (26.9%) [41]. These differences between our study and these others could also be related to the use of different methodologies to assess OD, or to different phenotypical characteristics of COVID-19 patients. The clinical test used (V-VST) in this study has excellent psychometrics (sensitivity 93.17%, specificity 81.39%, and inter-rater reliability Kappa = 0.77) [26,42] and was specifically adapted for the evaluation of COVID-19 patients [8].
In the first days of hospitalization, MN is common in COVID-19 due to appetite loss, systemic inflammation with increased hypermetabolism and muscle catabolism, and prolonged bed rest periods with disuse atrophy that is associated with muscle loss [33,43]. Our study identified many of these pathophysiological elements in the three waves of the pandemic, including anorexia (23.8%), vomiting and nausea (8.9%), diarrhea (30.1%) and reduced food intake (40.5%); respiratory failure requiring orotracheal intubation or ventilation with nasal intermittent positive pressure ventilation (12.2%); catabolic changes due the host inflammatory response phase; as well as high acute inflammation with CRP values between 7.7 and 10.2 mg/dL. Other authors have also reported 40% of patients with COVID-19 experiencing gastrointestinal symptoms such as nausea, vomiting, anorexia and diarrhea that can lead to MN [44], and that reduced food intake in these patients was associated with negative clinical outcomes [45]. Nutritional risk on admission in the patients in our series was extremely high (>98% in the 3 waves) according to the NRS-2002, a tool that has been validated to screen the risk of MN in hospitalized patients [30]. Other studies have found a similar percentage of patients with COVID-19 at nutritional risk (84.7-92%) [46,47], confirming the high impact of SARS-CoV-2 infection on nutritional status. On the other hand, assessment of MN with GLIM, recommended for COVID-19 patients [30], showed a high prevalence of MN in the first wave (45.9%) that was slightly reduced in the second (36.8%) and in the third (34.7; p < 0.05 vs. 1st wave). Regarding WL, we found highly significant differences when comparing the three waves: during the first wave, 36.8% of patients lost more than 6 kg during hospitalization with a mean WL of 6.5 ± 5.8 kg while these values were only 6.9% and 3.3 ± 4.2 kg, and 7.7% and 4.1 ± 4.3 kg in the second and third waves, respectively (percentage: p < 0.001; WL: 0.036). A review by Anker MS et al. 2021 [43] that included 589 patients from three studies reported a clinically notable WL (≥5%) in 37% of patients affected by COVID-19 during the first wave of the pandemic in 2020. Furthermore, we observed low albumin values and high levels of CRP and ferritin on admission among the three waves, as reported in other studies in 2021 [46]. Inflammatory status (CRP levels) improved on hospital discharge, as has been previously described [46,48]. These relevant improvements in nutritional status between the first, second and third waves, especially the impact on WL, are probably related to the implementation of a new nutritional systematic strategy "screen and treat" in COVID-19 wards after the first wave experience and that prioritized early nutritional supplementation before any assessment for MN. This new nutritional protocol, implemented from the second wave onwards, enabled an early, fast and generalized action to be taken. In the first wave we found that more than 95% of patients were at nutritional risk on admission, with 45% of patients diagnosed with malnutrition on discharge. The majority of patients were admitted with gastrointestinal symptoms, loss of appetite and previous WL, which required a quick response. For this reason, the "COVID-19 diet" was modified to be hypercaloric and hyperproteic and, in addition, all patients received two ONS a day systematically. They were then assessed during the first 24-48 h, and the diet was modified if necessary. This new protocol enabled generalized intervention in all patients admitted to our hospital with COVID-19. This kind of early and intensive nutritional treatment for COVID-19 patients has been recently recommended in a review on the topic, stating that "(t)argeted nutritional therapy should be started early in severe illness and sustained through to recovery if clinical and patient-centered outcomes are to be optimized" [33]. In addition, we have previously developed and applied a similar early intervention based on compensatory treatment for acute older patients with OD in order to reduce nutritional and respiratory complications. It is defined as the Minimal Massive Intervention (MMI), and is based on our previous scientific evidence and consists of: (a) fluid thickening (250 mPa·s and 800 mPa·s) [27] and textured modified diets (fork mashable or pureed diet) [32]; (b) caloric and protein ONS; and (c) oral health and hygiene recommendations during hospitalization and on discharge. Since the implementation of the MMI, there has been an improvement in nutritional status and functionality and a reduction in hospital readmissions, respiratory infections and mortality (NCT04581486) [8].
The clinical spectrum of patients infected with SARS-CoV-2 varies from mild clinical involvement to severe hypoxemia and pulmonary infiltrates. Up to 62% of patients in the study sample developed interstitial pneumonia, with significant differences between the second and third waves (68.0% vs. 57.2%; p < 0.05). Other studies have also reported high incidence of interstitial pneumonia, ranging from 53% to 91% [3,49]. These cases can worsen prognosis by pulmonary overinfection, due to bacteria residing in the oral cavity, which are capable of producing an additional bacterial pneumonia, the main etiological mechanism of which is aspiration, common in patients with OD. In our study, we found a prevalence of bacterial overinfection of 12.4%, 13% and 6.7% in the first, second, and third waves, respectively (p = 0.50). Regarding ICU admission, 8.2% of patients were admitted to ICU (p < 0.05 first wave vs. second and third), with a mean stay of 15.5 days (p < 0.001 first wave vs. second and third). We cannot attribute these higher figures during the first wave to the severity of the disease alone but also to the initial lack of knowledge in the management of COVID-19 by clinical staff. Other studies showed a higher percentage of ICU admission (17% and 26%) [3,49,50] with a similar median stay of 14 days. Of those patients in our study admitted to the ICU, 6.5% needed orotracheal intubation with the highest rate also in the 1st wave (10.7% vs. 5.1% 2nd wave, p < 0.05; and 3.5% 3rd wave, p < 0.01). Regarding hospital discharge, our patients remained at the hospital for a mean of 12.7 days, slightly less than that reported in a systematic review, which showed a mean of 14 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19) days [51]. Mortality found in the third wave was higher than in the first one (p < 0.01 vs. 1st wave); however, in the first wave we were not able to assess all patients in the first 24-48 h and many of them were not included in the study because they were admitted to the ICU very early and thus mortality in this wave is probably underestimated. In contrast, during the second and third waves, the screening and assessment was more systematic and exhaustive, and we ensured that almost all patients had both screening and assessment including those who were admitted to the ICU or died early, therefore increasing the mortality rates of our study. Other studies have shown disparate mortality prevalences: 34.0% during the first wave in Canada [49]; China (11.0%) [3]; and Spain (11.4%, 19.8% and 18.0%) [52][53][54]. Our mortality results are in line with these ranges.
Finally, we found that older age and poorer functional status were relevant indicators among COVID-19 patients and independently associated with OD and MN. In addition, each one of these conditions (swallowing impairment and poor nutritional status) was independently associated with each other, indicating their close relationship and the relevance of an early screening and treatment for both in order to improve patient general health status and avoid secondary complications. These results are in accordance with our previous studies on patients without COVID-19 with OD [8,[55][56][57] as well as with other authors [58][59][60]. Regarding intrahospital mortality, we found that old age, OD and MN were independently associated with this outcome indicating that a vulnerable status probably related to frailty could facilitate the non-recovery of the acute disease leading to this fatal outcome. A plausible reason for this is that these patients present age-related chronic medical conditions, frailty, comorbidities or sarcopenia [61] and/or lower immunity levels [61]. In addition, the age-dependent defects in B-cell and T-cell function and the excess production of type-2 cytokines could lead to prolonged proinflammatory responses and deficiency in control of viral replication, potentially leading to poor outcome [62]. OD and MN also play a key role in the functional and health deterioration of individuals as they are not able to safely acquire nutrients nor liquids to achieve the nutritional and hydric needs of the organisms, especially in a severe acute situation such as COVID-19 disease [33].

Conclusions
The COVID-19 patient phenotype in our sample was an adult patient over sixty years of age who came from the community and presented slight functional impairment before infection. On hospital admission, the prevalence of interstitial pneumonia was very high, as was the need for intensive respiratory therapy. Prevalence of OD, MN, severe loss in body weight, and mortality was also very high. In our study, OD was independently associated with MN and mortality. An early, systematic and proactive multimodal nutritional intervention including fluid thickening, texture modified diets and nutritional support improved patients' nutritional status. OD and MN are major issues among hospitalized COVID-19 patients and management of these two conditions should be prioritized and included in therapeutic protocols and guidelines for COVID-19 patients in order to improve their clinical outcomes during hospitalization.